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PubMed1994

Rhabdomyosarcoma of the tongue.

Although rhabdomyosarcoma (RMS) has a predilection for the head and neck region its occurrence in the tongue is uncommon. We report 2 cases of RMS of the tongue, 1 paediatric and 1 adult patient. The child who had RMS of the alveolar type involving anterior two-thirds of the tongue was treated with surgery and chemotherapy and is disease-free at 84 months of follow-up. The adult patient had locally extensive embryonal RMS of posterior third of the tongue, received chemotherapy and radiotherapy but died with progressive disease at 24 months of follow-up.

Adult↗
PubMed2026

FANCM is required for the PAX3::FOXO1-driven oncogenic program in rhabdomyosarcoma.

Many cancers are driven by mutationally altered transcription factors (TFs) that rewire cells to an oncogenic state. Cells must activate specific mechanisms to tolerate the burden of oncogenic TF activity. To define such mechanisms, we focused on a canonical oncogenic fusion protein-driven cancer, alveolar rhabdomyosarcoma (ARMS), where the PAX3::FOXO1 fusion protein hyperactivates and mislocalizes PAX3 and FOXO1 TF functions. Employing sequential functional genomic CRISPR-Cas9 screens, we identified FANCM, a DNA translocase in the Fanconi anemia pathway, as a selective dependency in PAX3::FOXO1+ ARMS. FANCM loss reduces fusion protein levels, induces myogenic differentiation, and disrupts the PAX3::FOXO1 transcriptional program, thereby halting oncogenic proliferation. Mechanistically, FANCM depletion exacerbates replication stress (RS) and DNA damage signaling, with chromatin-associated RS enriched at PAX3::FOXO1 target gene loci, resulting in selective downregulation of the oncogenic program. CRISPR exon-tiling screens prioritized FANCM's helicase and DNA-binding domains as essential for this dependency, linking FANCM-mediated replication fork binding to sustained oncogenesis.

ARMS↗
PubMed2026

Pleomorphic rhabdomyosarcoma, outcomes of patients with advanced disease treated with systemic agents: Retrospective study from the global pushing ultra-rare sarcomas towards hope (PUSH) consortium.

OBJECTIVES: To report the outcomes in adult patients with advanced pleomorphic rhabdomyosarcoma (P-RMS) treated with systemic therapy. METHODS: This global, multicenter, retrospective study conducted within the Pushing Ultra-Rare Sarcomas Towards Hope consortium (PUSH) included patients > 40 years with histologically confirmed advanced P-RMS, treated with at least one line of systemic therapy between 2013 and 2023. The primary endpoint was progression-free survival from first diagnosis of advanced disease, and from systemic treatment start (PFS-1 and PFS-2). Secondary endpoints included overall response rate (ORR), overall survival from first diagnosis of advanced disease and from treatment start (OS-1 and OS-2), and treatment-specific outcomes. RESULTS: Seventy-seven patients were included from 21 sarcoma reference centers. At a median follow-up of 44 months (IQR: 17.0-74.8), 49 (64%) patients had died and 48 (62%) had progressed. The median OS-1 and PFS-1 were 13.6 (95% confidence interval (CI): 9.4-22.5) and 5.4 (95% CI: 4.2-7.3) months, respectively. Two- and three-year OS-1 were 32.5% and 30.3%. Anthracycline-based regimens (n = 42) achieved a 50% ORR, with mPFS-2 and mOS-2 of 5.2 and 19.2 months; gemcitabine-based regimens (n = 15) a 42% ORR, with mPFS-2 and mOS-2 of 3.7 and 7.8 months; pazopanib (n = 6) a 33% ORR, with mPFS-2 and mOS-2 of 2.4 and 4.2 months; PD-1 inhibitors (n = 2) induced one response lasting 53 months. CONCLUSIONS: This series of advanced P-RMS treated with systemic agents, the largest available to date, showed meaningful activity of anthracycline- and gemcitabine-based regimens, and anecdotal responses to pazopanib and PD-1 inhibitors. Further prospective validation is planned.

Humans↗
PubMed2006

The challenging role of radiation therapy for very young children with rhabdomyosarcoma.

PURPOSE: To evaluate local control and toxicity for very young children treated with multimodality therapy for rhabdomyosarcoma (RMS). METHODS AND MATERIALS: From 1990 to 2004, 20 patients or=1 year after diagnosis (15) in terms of mild, moderate, or severe deficits. RESULTS: Median follow-up was 33 months for survivors and 23 months for all patients. Two-year actuarial local control, event-free survival, disease-specific survival, and overall survival were 84%, 52%, 74%, and 62%, respectively. All patients who began EBRT<or=18 weeks after the start of CMT had their disease controlled locally. Five have mild deficits and 10 have no deficits. CONCLUSIONS: A reduced dose of 36-Gy EBRT after delayed GTR may maximize local control while minimizing long-term sequelae for very young children with RMS, but unresectable tumors (e.g., parameningeal) require higher doses. Normal-tissue-sparing techniques such as intensity-modulated radiation therapy and IOHDR are encouraged. Local control may be maximized when EBRT begins <or=18 weeks after initiation of CMT, but further study is warranted. Longer follow-up is required to determine the full extent of late effects.

Age Factors↗
PubMed2004

Different pattern of matrix metalloproteinases expression in alveolar versus embryonal rhabdomyosarcoma.

BACKGROUND/PURPOSE: The matrix metalloproteinases (MMPs), a family of enzymes that degrade the extracellular matrix (ECM), are important in neoplastic cell invasion and metastasis. Data for rhabdomyosarcoma (RMS), the most frequent soft tissue sarcoma of childhood, are lacking. The aim of this study was to assess their expression in this tumor and to evaluate the correlation with clinicopathologic parameters. METHODS: Immunohistochemical expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, TIMP-1, and TIMP-2 was investigated in 33 human RMSs, 12 alveolar, and 21 embryonal histologic subtypes (12 high risk and 9 low/standard risk). Evaluation of the results was based on the percent of positive neoplastic cells and on staining intensity (negative, moderate, and strong). In situ zymography was carried out on 4 frozen RMS samples (2 alveolar and 2 high-risk embryonal). RESULTS: Alveolar type showed a stronger MMP-1, -2 and -9 expression in comparison with embryonal (P = .006, P <.001, and P <.001, respectively). Intratumoral vessels and perivascular ECM were positive for MMP-9 in the majority of RMSs. Both TIMPs had negative results. CONCLUSIONS: Gelatinases MMP-2 and MMP-9 and collagenase MMP-1 overexpression seem to contribute to the more aggressive phenotype of alveolar rhabdomyoblastic cells. Further characterization of the expression of MMPs and consequent utilization of their inhibitors in aggressive alveolar RMSs might lead to the development of novel anticancer therapies.

Adolescent↗
PubMed2003

Volumetric considerations in radiotherapy for pediatric parameningeal rhabdomyosarcomas.

PURPOSE: To assess the influence of radiation volume on outcome in pediatric parameningeal rhabdomyosarcomas (PM-RMSs). METHODS AND MATERIALS: Thirty patients ranging in age from 2 to 18 years (median 6) with PM-RMS were treated at the Hospital of the University of Pennsylvania and the Children's Hospital of Philadelphia between August 1988 and December 1999. The histologic subtypes included embryonal (n = 26), alveolar (n = 3), and undifferentiated (n = 1). Twenty-seven patients had Group III and three had Group IV disease. Twenty-seven patients underwent biopsy only and three subtotal resection. All patients were treated with multiple-agent chemotherapy and external beam radiotherapy. In 8 patients, all of whom had intracranial tumor extension, the tumor and whole brain were treated as the initial volume. In the remaining patients, most of those treated before 1992 were treated to the prechemotherapy (CMT) tumor volume for the entire treatment up to the total dose, which ranged from 45 to 59.4 Gy (median dose 57.9). In contrast, patients treated after 1992 generally received radiation initially to the pre-CMT volume (30.6-40 Gy; median dose 36) followed by a conedown to the post-CMT volume to a final dose of 41.4-55.2 Gy (median 50.4). RESULTS: With a median follow-up of 6.2 years (range 2.1-13.3), the actuarial 5-year overall survival, progression-free survival, and local control rate for the entire group was 82%, 76%, and 76%, respectively. Seven failures and five deaths have been documented. In univariate analysis, histologic type, tumor size, and age at diagnosis were found to be predictive of overall survival and local control. No statistically significant difference in overall survival or local control was seen between patients who received a conedown to the post-CMT volume (n = 13) and patients in whom the pre-CMT volume was included for the entire treatment (n = 9). CONCLUSION: Radiotherapy delivered to children with PM-RMS using a shrinking field technique with a post-CMT volume boost was effective and appears to give results comparable to those of patients in whom the pre-CMT volume was treated for the entire course. The use of such tailored treatment fields is likely to lead to fewer late effects and warrants further investigation.

Adolescent↗
PubMed2003

Primary and metastatic rhabdomyosarcoma in the breast: report of two pediatric cases.

Rhabdomyosarcoma (RMS) is a common childhood malignancy which can rarely be located in the breast. Here, we report two pediatric cases of breast RMS, one primary, the other secondary involvement. Primary one is alveolar, and the other embryonal subtype. Imaging findings with ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) and a thorough review of literature are presented.

Adolescent↗
PubMed2000

Myogenin is a specific marker for rhabdomyosarcoma: an immunohistochemical study in paraffin-embedded tissues.

Myogenin belongs to a group of myogenic regulatory proteins whose expression determines commitment and differentiation of primitive mesenchymal cells into skeletal muscle. The expression of myogenin has been demonstrated to be extremely specific for rhabdomyoblastic differentiation, which makes it a useful marker in the differential diagnosis of rhabdomyosarcomas (RMS) from other malignant small round cell tumors of childhood. Commercially available antibodies capable of detecting myogenin in routinely processed formalin-fixed paraffin-embedded (FFPE) tissue are now available. In this study, we evaluated myogenin expression using the monoclonal myf-4 antibody (Novocastra Labs) on FFPE in a large number of pediatric tumors in order to define the clinical utility of this marker. A total of 119 tumors were studied. These included 48 alveolar RMS (ARMS), 20 embryonal RMS (ERMS), one spindle cell RMS, 16 Ewing's sarcomas (ES), six nephroblastomas, two ectomesenchymomas, seven precursor hematopoietic neoplasms, five olfactory neuroblastomas, three neuroblastomas, six desmoplastic small round cell tumors, and five rhabdoid tumors. Distinct nuclear staining for myogenin was noted in all 69 RMS. Notably, the number of positive tumor cells differed between the ARMS and ERMS. In ARMS, the majority of tumor cells (75 to 100%) were positive, in contrast to ERMS, in which the positivity ranged from rare + to 25% in all but three tumors. Additionally, myogenin positivity was seen in two of two ectomesenchymomas and in two nephroblastomas with myogenous differentiation. All other tumors were clearly negative. Our results indicate that staining for myogenin is an extremely reliable and specific marker for rhabdomyoblastic differentiation. It gives consistent and easily interpretable results in routinely fixed tissues.

Biomarkers, Tumor↗
PubMed1997

Allelotype of pediatric rhabdomyosarcoma.

An allelotype covering all autosomes was constructed for the embryonal form of childhood rhabdomyosarcoma (ERMS) in order to identify regions encompassing tumorsuppressor genes (TSG) involved in ERMS. Thusfar most studies were focussed on chromosome 11p15.5, which frequently shows loss of heterozygozity (LOH) in embryonal tumors like RMS and Wilms' tumor (WT). In this study we show that, besides LOH of chromosome 11p15.5 (72%), LOH of chromosome 16q was present in 54% of the tumors analysed. Delineation of these two regions shows that the smallest region of overlap (SRO) for chromosome 11 was between D11S988 and D11S922. This region, estimated to be 7 cM and 3-5 Mb, is also the location of the putative Wilms' tumor WT2 TSG. It contains several genes including IGF2 and potential tumorsuppressor genes like H19 and p57kip2, which might contribute to the carcinogenesis of RMS. Analysis of chromosome 16q LOH defined the SRO between D16S752 and D16S413. LOH of chromosome 16 is also found in other tumors, including WT. Our data suggest that genes involved in the development of RMS and WT may not only be similar for chromosome 11 but also for chromosome 16.

Alleles↗
PubMed2005

Vascular endothelial growth factor acts in an autocrine manner in rhabdomyosarcoma cell lines and can be inhibited with all-trans-retinoic acid.

Vascular endothelial growth factor (VEGF) is a potent signalling molecule that acts through two tyrosine kinase receptors, VEGFR1 and VEGFR2. The upregulation of VEGF and its receptors is important in tumour-associated angiogenesis; however, recent studies suggest that several tumour cells express VEGF receptors and may be influenced by autocrine VEGF signalling. Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, and is dependent on autocrine signalling for its growth. The alveolar subtype of RMS is often characterized by the presence of a PAX3-FKHR translocation, and when introduced into non-RMS cells, the resultant fusion protein induces expression of VEGFR1. In our study, we examined the expression of VEGF and its receptors in RMS, and autocrine effects of VEGF on cell growth. VEGF and receptor mRNA and protein were found to be expressed in RMS cells. Exogenous VEGF addition resulted in extracellular signal-regulated kinase-1/2 phosphorylation and cell proliferation, and both were reduced by VEGFR1 blockade. Growth was also slowed by VEGFR1 inhibitor alone. Treatment of RMS cells with all-trans-retinoic acid decreased VEGF secretion and slowed cell growth, which was rescued by VEGF. These data suggest that autocrine VEGF signalling likely influences RMS growth and its inhibition may be an effective treatment for RMS.

Autocrine Communication↗
PubMed2005

FOXO1a acts as a selective tumor suppressor in alveolar rhabdomyosarcoma.

Rhabdomyosarcoma (RMS), the most common pediatric soft-tissue sarcoma, has two major histological subtypes: embryonal RMS (ERMS), which has a favorable prognosis, and alveolar RMS (ARMS), which has a poor outcome. Although both forms of RMS express muscle cell-specific markers, only ARMS cells express PAX3-FOXO1a or PAX7-FOXO1a chimeric proteins. In mice, Pax3 and Pax7 play key roles in muscle cell development and differentiation, and FoxO1a regulates myoblast differentiation and fusion; thus, the aberrant regulation of these proteins may contribute to the development of ARMS. In this paper, we report that FOXO1a is not expressed in primary ARMS tumors or ARMS-derived tumor cell lines and that restoration of FOXO1a expression in ARMS cells is sufficient to induce cell cycle arrest and apoptosis. Strikingly, the effects of FOXO1a are selective, as enforced expression of FOXO1a in ERMS-derived tumor cell lines had no effect. Furthermore, FOXO1a induced apoptosis in ARMS by directly activating the transcription of caspase-3. We conclude that FOXO1a is a potent and specific tumor suppressor in ARMS, suggesting that agents that restore or augment FOXO1a activity may be effective as ARMS therapeutics.

Animals↗
PubMed2006

Plakoglobin is differentially expressed in alveolar and embryonal rhabdomyosarcoma and is regulated by DNA methylation and histone acetylation.

Plakoglobin (gamma-catenin) and beta-catenin are pivotal components of cell-cell adherent junctions that link cadherin receptors to the actin cytoskeleton. Whereas beta-catenin overexpression induces cell proliferation and tumor formation, plakoglobin induces tumor suppressor activity. We investigated the expression of plakoglobin in alveolar (ARMS) and embryonal (ERMS) rhabdomyosarcoma (RMS) cell lines and tumors, and found that plakoglobin is present both in the cytoplasm and in the nucleus of ERMS cells, whereas it is absent or detectable at extremely low levels in ARMS. As gene silencing can be mediated by methylation and/or deacetylation of promoter regions, we assessed the effects of the DNA demethylating agent 5-Aza-2'-deoxycytidine (5AzadC) and of the histone deacetylase inhibitor Trichostatin A (TSA), and obtained restoration of plakoglobin expression in ARMS cells cultivated in the presence of 5AzadC and TSA. By methylation-specific PCR, ARMS cells were shown to contain methylated CpG dinucleotides in CpG islands located around the transcriptional start site of one or both alleles, whereas ERMS cells did not. Furthermore, we demonstrated that promoter regions (P1-P3) of plakoglobin gene were associated with hypoacetylated H4 histone in ARMS cells RH4, suggesting that aberrant DNA methylation of the 5' CpG island and histone deacetylation play key roles in silencing the plakoglobin gene. These results demonstrate that plakoglobin is differentially expressed in ARMS and ERMS and that its expression depends on the methylation and acetylation status of the gene.

Acetylation↗
PubMed1998

Polymerase chain reaction-based diagnosis of rhabdomyosarcomas: comparison of fetal type acetylcholine receptor subunits and myogenin.

The diagnosis of rhabdomyosarcoma (RMS) is usually straight-forward when light microscopy and immunohistochemistry are used. However, tumors that exhibit a low degree of differentiation and small biopsies can lead to confusion. In such patients and for the detection of minimal (residual) disease, a polymerase chain reaction (PCR)-based approach would be a valuable diagnostic adjunct. This type of approach would be highly sensitive and should be free from the risk for contamination of the tumor sample with normal tissue. Because myogenin and the alpha and gamma subunit of the fetal type acetylcholine receptor (AChR) are specific immunohistochemical markers for RMS, their expression on the mRNA level in RMS, other childhood and adult tumors, and normal tissues was studied. Although the sensitivity of both approaches was 100% in embryonal and alveolar RMS, detection of myogenin mRNA was not specific for RMS but occurred in normal muscle and the majority of the other normal tissues and childhood tumors. Conversely, detection of fetal AChR mRNA as defined by an alpha/tau ratio of < 1 was encountered only in RMS and denervated muscle. The authors conclude that mRNA of the fetal type AChR but not myogenin is a highly specific and sensitive target for the PCR-based diagnosis of RMS.

Adolescent↗
PubMed2006

Immunohistochemical detection of myogenin and p21 in methylcholanthrene-induced mouse rhabdomyosarcomas.

3-Methylcholanthrene (MC)-induced 10 embryonal (ERSs) and 24 pleomorphic rhabdomyosarcomas (PRSs) of the dermis in mouse were examined immunohistochemically for myogenin, p21 and proliferating cell nuclear antigen (PCNA) nuclear reactivity and myosin reactivity. ERSs had higher expression of myogenin and p21 compared with that of myosin. PRSs were divided into two groups having high (moderate or marked reactivity; HLM) and low (mild reactivity; LLM) levels of myosin expression. Expression of p21 was higher in HLM-PRSs than in LLM-PRSs. Statistically significant association was observed between myosin and p21 expression in PRSs, but not between myosin and myogenin expression. Myogenin and p21 reactivity were observed in myoblast-like cells, but rarely in multinucleated cells. In ERSs, small undifferentiated myogenic precursor cells were also positive for p21. No difference of PCNA reactivity was observed between HLM-PRSs and LLM-PRSs, although its reactivity was higher in PRSs than in ERSs. The results suggest that myogenin is related to myoblast-like cell differentiation in PRSs and that p21 plays essential roles in myotube formation and myosin expression. In ERSs, p21 may be involved in inhibition of myogenic precursor cell proliferation and differentiation.

Animals↗
PubMed1965

ELECTRON MICROSCOPY OF A RHABDOMYOSARCOMA OF THE EAR.

The fine structure of a case of differentiated rhabdomyosarcoma of the ear is described. Characteristic actomyosin filaments have been demonstrated in thin sections showing cross-striation (Z bands). There were large numbers of ribonucleoprotein particles but no virus-like particles present. It is hoped that, as in other difficult or rare tumours, electron microscopy may provide an additional clue of some assistance to the pathologist in determining diagnosis or aetiology.

Ear, External↗
PubMed2003

Myogenin and MyoD1 expression in paediatric rhabdomyosarcomas.

The diagnosis of paediatric solid tumours is often based on small tissue needle biopsies in which many different entities demonstrate a "small round cell tumour" phenotype and in which there may be insufficient tissue to allow the interpretation of diagnostic architectural features, which may be present in larger specimens. Therefore, the extensive use of a panel of immunohistochemical markers is part of the routine handling and investigation of such biopsies to reach a definite diagnosis. However, in some cases the morphological and routine immunohistochemical findings may be insufficient for a precise diagnosis or they may be difficult to interpret in the given clinical context. Although many paediatric tumours exhibit characteristic chromosomal translocations with resultant specific fusion transcripts, these require molecular methods for their detection, usually on fresh tissue samples, which may not always be available. As more immunohistochemical markers become available, more precise diagnosis on such small biopsies may be possible. This review examines the use of the immunohistochemical markers, MyoD1 and myogenin, in the diagnosis of paediatric rhabdomyosarcoma, including its subtypes.

Biomarkers, Tumor↗
PubMed2006

Validation of met as a therapeutic target in alveolar and embryonal rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is a highly malignant soft-tissue tumor of childhood deriving from skeletal muscle cells. RMS can be classified in two major histologic subtypes: embryonal (ERMS) and alveolar (ARMS), the latter being characterized by the PAX3/7-FKHR translocation. Here we first investigated whether the Met receptor, a transcriptional target of PAX3 and PAX7, has a role in PAX3-FKHR-mediated transformation. Following PAX3-FKHR transduction, Met was up-regulated in mouse embryonal fibroblasts (MEF), NIH 3T3 and C2C12 cells, and they all acquired anchorage independence. This property was lost in low serum but addition of hepatocyte growth factor/scatter factor (HGF/SF) rescued soft-agar growth. Genetic proof that Met is necessary for this PAX3-FKHR-mediated effect was obtained by transducing with PAX3-FKHR MEFs derived from Met mutant (Met(D/D)) and wild-type (Met(+/+)) embryos. Only Met(+/+) MEFs acquired anchorage-independent growth whereas PAX3-FKHR-transduced Met(D/D) cells were unable to form colonies in soft agar. To verify if Met had a role in RMS maintenance, we silenced the receptor by transducing ERMS and ARMS cell lines with an inducible lentivirus expressing an anti-Met short hairpin RNA (shRNA). Met down-regulation significantly affected RMS cells proliferation, survival, invasiveness, and anchorage-independent growth. Finally, induction of the Met-directed shRNA promoted a dramatic reduction of tumor mass in a xenograft model of RMS. Our data show that both ARMS- and ERMS-derived cell lines, in spite of the genetic drift which may have occurred in years of culture, seem to have retained an "addiction" to the Met oncogene and suggest that Met may represent a target of choice to develop novel therapeutic strategies for ARMS.

Animals↗
PubMed1998

Polysialylated neural cell adhesion molecule in childhood rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) cells express the polysialylated (PSA) form of the neural cell adhesion molecule (NCAM). During embryogenesis, PSA-NCAM is widespread and dynamically regulates embryonal developing processes, whereas postnatally, PSA-NCAM becomes restricted to a few regions of neural plasticity and regenerating neural tissues. Recently, PSA-NCAM has been shown to be a diagnostic and prognostic marker in adult patients with small cell lung cancer and multiple myeloma, both PSA-NCAM-expressing tumors. In this study, we determined the amount of PSA-NCAM in tumor specimens of nine children with different histologic types and clinical stages of RMS immunohistochemically, using the polysialic acid-specific MAb 735. In seven children, serum levels were investigated by an immunoluminescence assay using the same MAb. Patients with extensive disease showed strong staining of the tumor specimens, whereas patients with limited stages or after chemotherapy had distinctly a lesser amount of PSA-NCAM or almost no staining. Simultaneously, the serum levels were very high (up to 9-fold) in patients with extensive disease, whereas patients with limited disease or after successful therapy had normal serum levels. We conclude that PSA-NCAM expression is high in tumor specimens and serum of patients with advanced stages of RMS and decreases during successful therapy. PSA-NCAM might therefore serve as a marker for diagnosis and monitoring childhood RMS.

Adult↗